Guidelines Urge Proactive De-Labeling of Penicillin Allergy

Esther Landhuis

February 27, 2023

When seeing a patient whose chart notes a penicillin allergy, allergists should be diligent about initiating a conversation, David Khan, MD, told attendees of a presidential plenary session at the American Academy of Allergy, Asthma & Immunology (AAAAI) 2023 Annual Meeting in San Antonio, Texas.

There's a high chance that the patient is not allergic, and often "they are interested in finding out — especially if you tell them the downsides of carrying that label," said Khan, professor of internal medicine and pediatrics at the University of Texas Southwestern Medical Center in Dallas and current AAAAI president.

About a tenth of the population in the US has a documented penicillin allergy. The label carries significant risk — including two- to fourfold greater chances of MRSA and C. difficile infections and 14% increased risk of death — plus societal burden from increased prescribing of broad-spectrum antibiotic alternatives. Yet growing evidence suggests that some 90% of patients who report penicillin allergies can actually tolerate the antibiotic.

The AAAAI and American College of Asthma, Allergy, and Immunology (ACAAI) now recommend against penicillin skin testing prior to direct amoxicillin challenge in children with a history of benign skin reaction, Khan said in his presentation, which summarized key points from a practice parameter update published in December 2022 by an expert workgroup he chaired.

The concept of proactive de-labeling emerged a decade ago, Khan said, when nurses at the busy allergy clinic of the Montreal Children's Hospital in Quebec, Canada, noticed that children with a reported penicillin allergy typically had negative skin tests. Time-pressed, the nurses asked pediatric allergist Moshe Ben-Shoshan, MD, if they could skip the skin testing and just give amoxicillin, a penicillin antibiotic, in an oral challenge.

Lo and behold, when they approached 818 toddlers with suspected penicillin allergy, 94% passed the challenge. The team conducted a larger study, published in 2021, and saw a nearly identical pass rate. What's more, the children tolerated the antibiotic shortly after (median, 1.1 years) getting the allergy label, suggesting "this is probably not the natural history" and "they never had the allergy to begin with," Khan said.

"It's encouraging to us, as allergists, that we can test these kids pretty quickly. We don't have to wait 5 years like we did in the past," said Ellen Stephen, MD, an allergy/immunology fellow at Rush University Medical Center in Chicago, Illinois, in an interview with Medscape Medical News after the plenary.

De-Labeling Adults

In the adult population, Khan said, allergists should consider a direct amoxicillin challenge for patients with low-risk histories — those with benign skin reactions that occurred some years ago. The research in adults is "not quite as robust" as it is in children, so it's "more of a suggestion," Khan said. Still, he added, "many centers and many allergists are now adopting this as a way of streamlining the approach to de-labeling adults."

Clinical decision-making tools can help allergists identify low-risk adults to triage for direct challenge. One such tool, developed in Australia and validated in separate cohorts in Australia and the US, calculates a risk score using the mnemonic PEN-FAST:

  • 2 points if the suspected reaction to penicillin occurred ≤ 5 years ago

  • 2 points for anaphylaxis/angioedema or severe cutaneous adverse reaction

  • 1 point if the reaction required treatment

Research presented on an AAAAI poster by Chang Su, MD, and Jason Kwah, MD, of Yale School of Medicine validates PEN-FAST in an additional US cohort. Among the study's 117 adults with reported penicillin allergy, 86 (73.5%) had PEN-FAST scores ≤ 2, and all of these low-risk patients passed the oral challenge.

Such tools can encourage penicillin allergy de-labeling by helping to "quantify the risk for the patient when discussing the plan of care," said Stephen.

At AAAAI, Khan discussed other considerations for de-labeling penicillin allergy:

  • Piperacillin-tazobactam allergy. About two thirds of patients with suspected allergy to this broad-spectrum penicillin can tolerate other forms of penicillin. This means that if allergists are trying to de-label these patients by doing penicillin skin testing and amoxicillin challenge, "you're going to miss them," Khan said. "You need to test them directly with the pip-tazo."

  • Cephalosporin for non-anaphylactic penicillin allergy. Less than 5% of patients with an unverified penicillin allergy are truly allergic, and of those, only ~2% will cross-react to cephalosporin, a related beta-lactam antibiotic. So "if the history is unverified penicillin allergy that is non-anaphylactic — which, frankly, is probably 99% of your patients — they can receive any cephalosporin without any testing whatsoever," Khan said. "This is going to be a huge game changer."

  • Cefazolin and ceftibuten for anaphylactic penicillin allergy. Even in patients with anaphylaxis to penicillin, allergists can administer a non-cross-reactive cephalosporin, such as cefazolin or ceftibuten, without prior testing.

Khan has received financial support from UpToDate and Aimmune; serves on the AAAAI Board of Directors, as the American College of Asthma, Allergy, and Immunology (ACAAI) chair of literature review, as co-chair of AAAAI/ACAAI Conjoint Board Review Committee, and as the Texas Allergy, Asthma, and Immunology Society's Meetings Committee chair; and is associate editor of the Journal of Allergy and Clinical Immunology In Practice.

American Academy of Allergy, Asthma & Immunology (AAAAI) 2023 Annual Meeting: Presidential plenary session 1601 and Poster 185. Presented February 24 and 25, 2023.

Esther Landhuis is a freelance science & health journalist in the San Francisco Bay Area. She can be found on Twitter @elandhuis.

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